Effects of exercise on cancer-related fatigue

Abstract

Cancer patients frequently suffer from fatigue and loss of physical performance. Several biologic, psychologic, and social factors have been suggested as explanations for the origins of fatigue in this context. In most cases, fatigue has a multifactorial genesis. However, recent studies suggest that fatigue may originate from alterations in the muscular energetic systems caused by cancer and its treatment. Furthermore, there is growing evidence that physical exercise programs help prevent the manifestation and reduce the intensity of cancer-related fatigue. In this article, actual evidence of the relationship between fatigue and impairment of physical performance in cancer patients and suggestions for new directions for research are discussed. Cancer 2001;92:1689–93. © 2001 American Cancer Society.

Fatigue is one of the most common problems experienced by cancer patients. Several studies have reported that this symptom affects up to 70% of patients during chemotherapy and radiotherapy.1–3 Furthermore, fatigue may turn into a long-lasting problem: about 30% of cancer survivors report that the impairment of physical functioning persists for years after the end of therapy.4–6 Finally, fatigue may be severe enough to prevent patients from carrying out normal daily activities or going back to work following treatment. Therefore, this symptom may have devastating economic and social consequences for patients.

Fatigue is a normal and necessary instrument of physiologic self-regulation. This symptom usually appears after intense or prolonged activities and protects the body from exaggerated or harmful efforts. However, fatigue becomes pathologic when it appears during normal activities, persists for long periods, does not improve after rest, or becomes severe enough to force patients to reduce their level of activity.7

Several etiologic mechanisms have been postulated to explain the development of fatigue in cancer patients, including pain, electrolyte and fluid disturbances, anemia, impaired nutritional status, weight loss, changes in the concentration of metabolically active molecules as a result of the interaction between the tumor and the host defense system, intercurrent systemic pathology, drugs with action on the central nervous system, and sleep disturbances.1, 8 Psychologic factors may also play an important etiologic role in the genesis of cancer fatigue. Nerenz et al. found a strong relationship between tiredness and the emotional distress experienced during treatment.9 In particular, depression is considered to be a contributor to fatigue in cancer patients. We have reported that poor physical performance is related to more severe depression and anxiety and to higher intensity of somatic complaints.10 Two reports described an association between fatigue and depression in cancer patients undergoing radiotherapy or chemotherapy;11, 12 a further study demonstrated a strong correlation between impaired performance status and depression in lymphoma patients evaluated several years after treatment.5

However, no consistent association has been established between physical or psychologic variables and the severity of fatigue. Therefore, the actual causes of this symptom in cancer patients are not fully understood. Most authors agree that the origin of cancer-related fatigue is multifactorial. Moreover, the interaction between the various etiologic mechanisms is complex.

In fact, fatigue represents only one side of the problem of physical impairment experienced by cancer patients. Fatigue is usually defined as a feeling of weariness, tiredness, or lack of energy. However, fatigue can affect several dimensions of the patient's life. Thus, patients may describe the problem in different ways: as a lack of concentration and loss of memory (mental fatigue), an inability to begin tasks or a tendency to avoid social contacts and activities (volitional fatigue), or tiredness and easy exhaustion from activities requiring physical effort (physical fatigue). While the first two forms of fatigue may primarily indicate psychologic disturbance and increased mental distress, the physical fatigue experienced by cancer patients usually has an organic etiology.

Physical fatigue frequently results from alterations in the muscular energetic systems caused by cancer treatment. The muscle cells obtain energy for work via two metabolic pathways. In the first one, carbohydrates and fats are completely oxidated to water and carbon dioxide in the mitochondria; the energy obtained is stored in the cells as adenosine triphosphate (ATP). This process can only be carried out in the presence of oxygen and is therefore called aerobic. When the oxygen supply is reduced, the cells produce energy through the second metabolic pathway, called anaerobic glycolysis. In this process, glucose is incompletely metabolized, resulting in the production of ATP and lactic acid.

The supply of oxygen to the mitochondrial crests is the critical factor in the regulation of energy production. Adequate oxygen delivery to the cells requires the integrity of all links in a complex chain of organs and functions regulating oxygen absorption, transport, and release. Several functional and anatomic changes due to cancer treatment can affect the oxygen supply to the cells. Alterations of the bronchial tree, lung and plasma volume, pulmonary perfusion, alveolar surface, heart function, red blood cell count, and concentration of oxidative enzymes in the muscle cells can all result in reduced oxygen transport and utilization. Therefore, cancer and its therapy can produce an impairment of oxygen delivery through the aerobic energy production pathway by different physiopathologic mechanisms.

Chemotherapy can damage bone marrow and therefore impair the production of red blood cells. The resulting anemia decreases the oxygen transport capacity of the blood and hence the oxygen supply to the cells. Cardiotoxic cytostatic agents like anthracyclines and cyclophosphamide can cause a reduction of cardiac output and therefore an impairment of the blood supply to the muscles. Loss of lung volume caused by disease (i.e., lung metastases and pleural effusion) or as a sequel of treatment (lobectomy, lung fibrosis after radiotherapy) results in an alteration of the ventilation-perfusion ratio, causing further impairment in blood oxygenation.

All these factors contribute to a reduction in oxygen delivery to the cells and limit the availability of oxygen for utilization in the synthesis of ATP at the mitochondrial crests. Thus, more cardiac and respiratory work, and hence a higher energy consumption, are needed to sustain an adequate oxygen supply to the cells during rest and physical work. However, because the maximal oxygen uptake is severely impaired as a consequence of disease and treatment, the oxygen transport systems can be overwhelmed even by normal daily activities like climbing stairs, walking, or housekeeping. Therefore, cells obtain energy through anaerobic glycolysis. This system produces less ATP per mole of glucose (3 moles) than aerobic oxidation (38 moles). Furthermore, its end product, lactic acid, accumulates in the cells and reduces intracellular and interstitial pH, leading to additional metabolic stress. The combined burden of a long-lasting increase in heart rate and respiratory work, less effective energy production, and metabolic acidosis can lead to tiredness, reduced stamina, and the inability to carry out any intense physical effort.

The metabolic distress of cancer patients experiencing fatigue may be substantially increased during low-intensity physical activities. We evaluated the heart rate and lactic acid concentration in cancer patients with severe, long-lasting fatigue during a submaximal effort. The symptom had been present for a time ranging between 5 weeks and 18 months and prevented the patients from carrying out normal daily activities. Patients in the study walked on a treadmill at a speed of 5 km/hour for 3 minutes. This submaximal effort led to a dramatic increase in their heart rate (mean, 138 heartbeats per minute) and lactic acid concentration (mean, 2.6 mmol/L).13 As a consequence of this increased metabolic distress, patients were unable to carry out normal daily activities.

Two studies have provided substantial evidence that cancer patients may have a decline in neuromuscular efficiency. In the first study, the authors evaluated neuromuscular fatigue of the tibialis anterior muscle, cardiopulmonary fitness, and severity of fatigue in 13 men with prostate cancer before and after radiation. During this time, a significant decline in neuromuscular efficiency was observed. The authors suggest that this phenomenon may be attributed to an increased release of cytokines as a consequence of tissue necrosis after radiotherapy; however, no objective data were provided to support this hypothesis.14 In another study, Bruera et al. evaluated the muscular function of patients with advanced breast cancer as well as healthy persons. Patients had several muscular alterations, including lower maximum strength after supramaximal stimulation, reduced relaxation velocity, and a higher loss of contractile strength, after 30 seconds of stimulation.15 These provocative findings suggest that cancer or its treatment may exert specific alterations in muscular function.

The phenomenon of impaired muscular function can be aggravated by the lack of activity during in-hospital treatment. Prolonged bed rest results in a substantial loss of muscle mass and plasma volume and a reduction of cardiac output that further impairs work capacity.16–18 After discharge, patients consequently need to make greater efforts to carry out normal activities. Furthermore, treatment with high-dose corticoids results in a substantial loss of muscle mass. Finally, immunosuppression with cyclosporine may result in mitochondrial myopathy19 and loss of capillary density and exercise ability.20 These last phenomena are clinically indistinguishable from the changes generated by physical deconditioning.

Since the cause of fatigue in cancer patients is unknown, approaches to treating this symptom have been eclectic. A number of behavioral and psychologic therapies (relaxation training, self-hypnosis, biofeedback, support groups) have been proposed for the treatment of cancer-related fatigue. Two reports mention positive effects of individual and group psychotherapy on the fatigue of cancer patients undergoing radiotherapy. These results are promising; however, no studies have evaluated the effects of these interventions in other clinical settings.21, 22

Pharmacologic treatment of cancer-related fatigue has not shown convincing results. This can be partially explained by the fact that cancer-related fatigue, as described above, frequently results in impairment of physical performance, and cellular energy production cannot be improved by pharmacologic means.

For many years, the physician's recommendation to cancer patients has been to rest and avoid physical effort. These recommendations were empiric: because the disease and its treatment are associated with functional changes resulting in impaired physical performance, exercise may generate symptoms like fatigue, breathlessness, and tachycardia. Therefore, avoiding strenuous activities results in less discomfort. However, a reduced level of exercise can cause a paradoxic outcome. As mentioned earlier, inactivity induces further muscular wasting and loss of cardiorespiratory fitness. Hence, a lack of physical activity creates a self-perpetuating condition of diminished activity leading to easy fatigue, and vice versa. This mechanism could explain the persistence of fatigue and impairment of physical performance in some patients even years after the end of treatment.

In recent years, scientific evidence has dramatically changed our ideas about the relationships among physical activity, rest, and cancer-related fatigue. Several studies have reported that exercise can prevent the manifestation and reduce the intensity of fatigue in cancer patients during and after treatment. This approach may appear counterintuitive; however, physical activity produces adaptive changes such as gains in muscle mass and plasma volume, improved lung ventilation and perfusion, increased cardiac reserve, and a higher concentration of oxidative muscle enzymes. Furthermore, resistance exercises have been shown to reduce the loss of muscle mass related to corticoid treatment.23, 24 These changes are the opposite of the impairment resulting from cancer and treatment. Therefore, exercise can result in a reduction of fatigue by normalizing physical performance.

The positive effects of exercise in cancer patients were described for the first time by Winningham in 1983.25 In her study, 10-week bicycle ergometer training program of 30 minutes, 3 times per week, produced a substantial increase in physical performance of breast cancer patients undergoing chemotherapy, compared with control patients who did not train. In further studies, Winningham, MacVicar, et al. showed that an exercise program reduced mood disturbance, somatic complaints,26 total body weight, and body fat percentage,27 and increased the maximal physical performance of women with breast cancer undergoing chemotherapy.

In recent studies, exercise has also been shown to improve physical performance in cancer patients undergoing myeloablative therapies. In the first study, 20 patients participated in an exercise program after bone marrow transplantation. It consisted of walking on a treadmill 30 minutes daily for 6 weeks. By the end of the training program, the physical performance of all patients had improved substantially. Furthermore, heart rate and lactate concentration decreased significantly during walking at a submaximal speed of 5 km/hour.28

In a controlled, randomized study, patients who carried out a 6-week endurance training program after high-dose chemotherapy (HDC) and peripheral blood stem cell transplantation (PBSCT) had a significantly higher maximal physical performance and lower fatigue scores than patients who did not train.29 In addition, at the end of the training program, patients in the training group had significantly higher hemoglobin concentrations than patients in the control group. This finding may seem surprising, but exercise has been shown to increase the hemoglobin concentration in patients with severe anemia due to chronic renal failure.30, 31 These data suggest that endurance exercise may activate the production and release of hematopoietic growth factors.

In two recent studies, an endurance training program consisting of bicycling for 30 minutes daily using a bed ergometer significantly reduced the loss of physical performance32 and fatigue33 during the hospitalization of cancer patients undergoing HDC and PBSCT. Also, chemotherapy-related complications, duration of aplasia (absolute neutrophil count < 500/mL and thrombocytes < 20,000/mL), and duration of hospitalization were significantly reduced in the training group compared with controls who did not train.

The effects of physical activity are not limited to better cardiovascular or muscular function. Indeed, the improvement of physical performance can increase the feeling of control, independence, and self-esteem of patients; this improved self-confidence can result in better social interaction and a reduction in anxiety and fear. Therefore, physical activity also can result in secondary benefits, such as an improved mood state. We frequently observe that patients participating in a training program are more self-confident and have an improved mood as exercise leads them to a better performance status and thus to higher levels of physical independence.

Endurance exercise is a promising new approach to treating cancer-related fatigue. Further studies are warranted to assess the effects of exercise programs in other settings. These studies should evaluate the effect of physical activity in patient populations at high risk for developing severe or long-lasting fatigue (e.g., patients with hematologic malignancies undergoing conventional chemotherapy or radiotherapy over large areas, patients undergoing bone marrow transplantation, and patients who have undergone extensive gastrointestinal or lung resections due to primary or metastatic disease). Moreover, there are no data about the effects of other exercise forms besides endurance training on the well-being and physical performance of cancer patients. Resistance training, for instance, has been shown to reduce the loss of muscle mass in patients receiving high-dose corticoids.23, 24 There is no information about the feasibility and effects of exercise programs during different chemotherapy protocols. Finally, some evidence suggests that physical activity can have an effect on the immune system.34, 35 Therefore, randomized studies should evaluate the effect of exercise on immune function and how it correlates with the incidence and severity of infection in cancer patients in different settings.